[unreadable] Iron the most abundant transition metal in living organisms can be released from tissues during injury. Accumulation of released catalytic reactive iron has been demonstrated in a number of diseased lungs, for examples, ARDS and cystic fibrosis. Conversely, sequestration of iron in a catalytically less reactive form is fundamentally important in lung defense. Better and more effective iron-chelating drugs, which do not inflict damage on healthy tissues, have not been developed. A lack of knowledge of iron metabolism in the lung hampers a complete understanding of its role in both normal and diseased states, and precludes the development of a lung-specific therapeutic intervention. Our long-term goal is to understand the molecular mechanisms involved in the maintenance of normal iron homeostasis in the lung. Our central hypothesis is that two recently identified transmembrane iron transporters, DMT1 (divalent metal transporter 1) and MTP1 (metal transporter protein 1), are key constituents of a novel mechanism for the detoxification of iron in the lung. In this process, iron is taken up by lung cells via DMT1-mediated transfer and re-exported by the same cells in less harmful protein-bound forms via MTP1-mediated pathway. This hypothesis is formulated based on the data from our laboratories that include 1) DMT1 and MTP1 genes are activated by iron in airway epithelial cells and alveolar macrophages, 2) the levels of DMT1 and MTP1 are elevated after endotoxin exposure and in some diseased lungs, 3) MTP1 protein is localized uniquely to the apical membrane in airway epithelial cells, and 4) in human bronchial epithelial cells cultured on a porous membrane, elemental iron taken up across the apical surface by these cells is later re-released across the same apical surface in protein-bound forms. We will test our hypothesis using cultured airway epithelial cells and mutant mice defective in DMT1/MTP1 mediated iron transport. This study will lead to a better understanding of iron dysfunction in diseased lungs. [unreadable] [unreadable]